bims-metalz 2023-05-28 papers

Issue of 2023–05–28
five papers selected by
Mikaila Chetty, Goa University

J Alzheimers Dis Rep. 2023 ;7(1): 381-398

Common Signaling Pathways Involved in Alzheimer's Disease and Stroke: Two Faces of the Same Coin.

Tushar Kanti Das, Bhanu Priya Ganesh, Kaneez Fatima-Shad.

Alzheimer's disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are the disruption of neuronal circuitry at different levels of cellular signaling, leading to the death of neurons and glial cells in the brain. Therefore, it is necessary to find out the common molecular mechanisms of these two diseases to understand their etiological connections. Here, we summarized the most common signaling cascades including autotoxicity, ApoE4, insulin signaling, inflammation, mTOR-autophagy, notch signaling, and microbiota-gut-brain axis, present in both AD and IS. These targeted signaling pathways reveal a better understanding of AD and IS and could provide a distinguished platform to develop improved therapeutics for these diseases.

Keywords: Alzheimer’s disease; Apolipoprotein E; Notch signaling; PI3K/Akt; excitotoxicity; glucose; insulin; ischemic stroke; mTOR-autophagy; microbiota-gut-brain axis

DOI: https://doi.org/10.3233/ADR-220108

J Alzheimers Dis Rep. 2023 ;7(1): 415-431

Therapeutic Potential of Microbiota Modulation in Alzheimer's Disease: A Review of Preclinical Studies.

Carla Benichou Haziot, Kulbir Singh Birak.

Alzheimer's disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging.

Keywords: Alzheimer’s disease; brain-gut axis; dysbiosis; fecal microbiota transplantation; microglia; neurodegenerative diseases; probiotics; therapeutics

DOI: https://doi.org/10.3233/ADR-220097

Curr Opin Neurobiol. 2023 May 24. pii: S0959-4388(23)00055-7. [Epub ahead of print]81 102730

Functional effects of gut microbiota-derived metabolites in Alzheimer's disease.

Hyunjung Choi, Inhee Mook-Jung.

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aβ and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.

Keywords: Alzheimer's disease; Gut microbiota; Microbial metabolites

DOI: https://doi.org/10.1016/j.conb.2023.102730

Ann Med Surg (Lond). 2023 May;85(5): 1780-1783

The microbiota-gut-brain axis and three common neurological disorders: a mini-review.

Amjad Mhanna, Zuheir Alshehabi.

Neurological disorders are an important cause of disability and death globally. Recently, a large body of research shows that the gut microbiome affects the brain and its conditions, through the gut-brain axis. The purpose of this mini-review is to provide a brief overview of the relationship between the microbiota-gut-brain axis in three neurological disorders: epilepsy, Parkinson's disease, and migraine. The authors chose these three disorders because of their burdensome and great effect on health care. We live on a microbial planet. Before humans, microorganisms existed for a hundred million years. Today, there are trillions of these microbes living in our bodies, it is called human microbiota. These organisms have a crucial role in our homeostasis and survival. Most of the human microbiota live in the gut. The number of gut microbiota is much more than the number of body cells. Gut microbiota has been regarded as a crucial regulator of the gut-brain axis. The discovery of the microbiota-gut-brain axis is described as a major advancement in neuroscience because it influences the pathophysiology of several neurological and psychiatric disorders. From this, more studies of the microbiota-gut-brain axis are needed in the future, to provide a better understanding of brain disorders and so that better treatment and prognosis.

Keywords: epilepsy; gut-brain-axis; microbiota; migraine; parkinson’s disease

DOI: https://doi.org/10.1097/MS9.0000000000000552

Drug Res (Stuttg). 2023 May 23.

Ferulic Acid: Signaling Pathways in Aging.

Deepa Neopane, Vaseem Ahamad Ansari, Aditya Singh.

The need for clinical remedies to the multiple age-related deficiencies in skin function brought on by extrinsic and intrinsic causes is increased by these demographic changes. Reactive oxygen species (ROS), mitochondrial deoxyribonucleic acid (mtDNA) mutations, telomere shortening, as well as other factors, contribute to the aging of the skin. In this overview, the issue of human skin aging is introduced, along with several pathways and the protective effects of ferulic acid in light of current patents. The complex antioxidant effect of ferulic acid depends on the "sweeping" away of free radicals as well as the suppression of the synthesis of ROS or nitrogen. Furthermore, Cu (II) or Fe protonated metal ions are chelated by this acid (II). Ferulic acid is a free radical scavenger as well as an enzyme inhibitor, increasing the activity of enzymes that scavenge free radicals while decreasing the activity of enzymes that speed up the creation of free radicals. AMPK signalling, which can regulate cellular homeostasis, stress tolerance, cell survival and proliferation, cell death, and autophagy, has recently been linked to aging and lifespan. Therefore, Caenorhabditis elegans (C. elegans) and rodents had longer life-spans due to specific AMPK activation. By inhibiting the TGF-β/Smad signalling pathway, UV irradiation can reduce the production of procollagen. Glycation changes the skin's physical characteristics, making it less elastic and stiffer. . Excessive free radicals simultaneously trigger the nuclear factor kappa B (NF- κB) signalling pathway, increasing TNF levels and matrix metalloproteinase production (MMPs).

DOI: https://doi.org/10.1055/a-2061-7129